Vertical sleeve gastrectomy (VSG), a surgical procedure for obese patients that reduces the stomach size, is rapidly effective in eliminating the dependence of type II diabetic patients on medications and produces long-lasting weight loss. The rapidity of the change in glucose metabolism suggests that changes in food intake and nutrient absorption are unlikely to be the sole mediators of the effects of VSG surgery. Indeed, patients or mice receiving VSG exhibit increased circulating bile acids, which are ligands for the nuclear receptor farnesyl X receptor (FXR). Ryan et al. performed VSG on wild-type mice and mice in which FXR was knocked out (KO) and found that weight loss and reduction in body fat were not maintained after VSG in the FXR-KO mice. Wild-type mice, but not FXR-KO mice, ate less food for the first 3 weeks after surgery and showed reduced preference for high-fat food. The FXR-KO mice also failed to show improved glucose tolerance after surgery. Bioinformatic analysis of the differences in mRNA abundance in the small intestine in wild-type and FXR-KO mice after VSG revealed alterations in pathways associated with lipid and bile acid metabolism and those that could be associated with changes in the gut microbiota. This result is consistent with the ability of bile acids to modulate the gut microbiota and with the ability of gut microbiota to modify bile acid composition through enzymatic activity. Analysis of samples from the large intestine from wild-type and FXR-KO mice showed that VSG had a larger overall effect on the gut microbiota in the wild-type mice and furthermore that changes in the gut microbiota associated with reduced weight gain or that were negatively associated with diabetes occurred only in the wild-type mice after VSG. Thus, FXR signaling and changes in the gut microbiota appear important for the short-term and long-term beneficial outcomes of VSG.